Drug resistance remains a major obstacle to prolonging the lives of cancer patients, including those with myeloma and leukemia. Recently, we have become more aware of the influence of the tumor microenvironment on tumor cell survival and growth. The central hypothesis of this application is that the tumor microenvironment provides a sanctuary for subpopulations of tumor cells to evade or circumvent drug-induced cell death and that this represents a form of de novo drug resistance. Furthermore, we believe that this form of de novo drug resistance is a major contributor to the development of minimal residual disease following initial treatment. The subpopulation of cells, or minimal residual disease, that survives initial treatment progresses to acquire complex mechanisms of drug resistance resulting in disease progression that is difficult to overcome. Focusing on hematologic malignancies, mainly multiple myeloma (MM), we propose that the bone marrow microenvironment, which includes extracellular matrices, stromal cells, and soluble factors, protects tumor cells from drug-induced cell death. Our initial work during the past funding period of this grant focused on the physical contact of tumor cells with the extracellular matrix protein, fibronectin (FN), and we coined the term "cell adhesion mediated drug resistance" (CAM-DR) to describe this phenotype. Recently, we have extended our work to include studies of tumor cell interaction with bone marrow stroma (BMS), and discovered that in addition to drug resistance mediated by physical contact, soluble factors (growth factors, and cytokines) produced by the tumor cell interactions with BMS also contribute to the drug resistant phenotype, thereby deriving the term "environment mediated drug resistance" or EMDR. In this grant proposal we will capitalize on our previous experience, to elucidate mechanisms of EMDR. Specific aims of this grant will a) use gene expression profiling to identify novel targets for sensitizing cancer cells residing in the bone marrow microenvironment to chemotherapy;b) examine the contribution of Stat3 pathway in mediating EMDR;and c) investigate the contribution of NF-kB in mediating EMDR using an in vivo mouse model of MM. Preventing or circumventing this form of de novo drug resistance will prevent or delay the emergence of acquired drug resistance by reducing the extent and occurrence of minimal residual disease.